It is well known that for vitamin D to express biological activity in regulating calcium and phosphate metabolism, it must be activated by enzymatic hydroxylation. In the case of vitamin D.sub.3 this metabolic activation sequence involves first a hydroxylation at carbon 25, occurring in liver tissue, and the resulting product, 25-hydroxyvitamin D.sub.3, is then further hydroxylated in the kidney to the 1.alpha.,25-dihydroxyvitamin D.sub.3 compound, which is generally considered the active hormonal form of the vitamin responsible for the regulation of calcium absorption and bone mineral deposition and resorption in the animal or human. Vitamin D.sub.2 undergoes the exactly analogous activation sequence. Thus 25-hydroxylation represents the first step in vitamin D activation, and indeed all subsequent known metabolic conversions utilize the 25-hydroxy derivative as the required substrate. Blocking this 25-hydroxylation step would, therefore, prevent vitamin D activation, and hence would abolish or at least diminish the expression of vitamin D biological activity. Suppression of vitamin D activity would be desired in situations such as hypercalcemia resulting from bone or neoplastic disease or from vitamin D intoxication, and compounds that effectively inhibit vitamin D metabolism are thus useful therapeutic agents for the correction or treatment of such pathological hypercalcemic conditions.
Vitamin D-related compounds capable of suppressing the 25-hydroxylation of vitamin D.sub.3 have been reported. These include, for example, a 25-aza-derivative (Onisko et al., J. Biol. Chem. 254, 3493 (1979)) and a 19-hydroxy-10,19-dihydro-vitamin D.sub.3 compound (Paaren et al., Biochemistry 19, 5335 (1980)); high doses of these metabolic antagonists are required, however, to achieve even partial inhibition.